Floxium

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLOXIUM®

Composition:

Active ingredient: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin – 500 mg;

Excipients: crospovidone (polyplasdone XL), microcrystalline cellulose, potato starch, talc, hypromellose (hydroxypropylmethylcellulose), sodium lauryl sulfate, sodium starch glycolate (type A), calcium stearate, coating mixture "Opadry II Yellow" 33G22507 (containing: triacetin; hypromellose; lactose monohydrate; titanium dioxide (E 171); polyethylene glycol; yellow iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets of creamy-yellow color, oval-shaped with a biconvex surface, with a score line on one side and embossing "KMP" on the other. A yellowish core is visible in cross-section.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01M A12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is characterized by a broad spectrum of antibacterial activity. The bactericidal effect is achieved through inhibition by levofloxacin of the bacterial enzyme DNA gyrase, which belongs to type II topoisomerases. This inhibition prevents bacterial DNA from transitioning from the relaxed to the supercoiled state, thereby making further division (reproduction) of bacterial cells impossible. The spectrum of activity of Floxium® includes Gram-positive and Gram-negative bacteria, including non-fermenting bacteria.

Typically susceptible species

Gram-positive aerobes: Bacillus anthracis, Staphylococcus aureus (methicillin-susceptible), Staphylococcus saprophyticus, Streptococci groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Gram-negative aerobes: Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobes: Peptostreptococcus.

Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species with possible acquired resistance

Gram-positive aerobes: Enterococcus faecalis, Staphylococcus aureus (methicillin-susceptible), coagulase-negative Staphylococcus spp.

Gram-negative aerobes: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobes: Bacteroides fragilis.

Naturally resistant strains

Gram-positive aerobes: Enterococcus faecium.

Mechanism of resistance development

Resistance to levofloxacin develops through stepwise mutations in the target site of both type II topoisomerases—DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as permeability (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance is observed between levofloxacin and other fluoroquinolones. Due to its mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents.

Antibiotic breakpoints (or breakpoint diameters of microbial growth inhibition zones)

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends the minimum inhibitory concentration (MIC) of levofloxacin for determining susceptibility of microorganisms, distinguishing between organisms that are "intermediate susceptible" and "intermediate resistant," as presented in Table 1 based on MIC testing (mg/L).

Table 1

EUCAST clinically defined MIC values for levofloxacin (version 2.0, 2012-01-01)

The prevalence of resistance may vary geographically and over time for individual species; therefore, local information on resistance is very important, especially in the treatment of severe infections. Expert advice should be sought when local resistance prevalence raises uncertainty regarding the appropriateness of using this agent, at least for certain types of infections.

Pharmacokinetics

Absorption. When administered orally, levofloxacin is rapidly and almost completely absorbed, with peak plasma concentrations reached within 1–2 hours after administration. Absolute bioavailability is 99–100%. Food intake has a minor effect on its absorption. Steady-state levels are achieved within 48 hours after administration of 500 mg once or twice daily.

Distribution. Approximately 30–40% of levofloxacin is protein-bound in plasma. The mean volume of distribution of levofloxacillin is approximately 100 L after single and repeated 500 mg doses, indicating good distribution into body tissues.

The accumulation effect of levofloxacin with a dosage regimen of 500 mg once daily is not clinically significant and can be disregarded. There is a slight but predictable accumulation with a dosage regimen of 500 mg twice daily. Steady-state distribution parameters are achieved within 3 days.

Distribution in bronchial mucosa and bronchial epithelial secretions. The peak concentration of levofloxacin in bronchial mucosa and bronchial epithelial secretions after an oral dose exceeding 500 mg is 8.3 and 10.8 µg/mL, respectively.

Distribution in lung tissue. The peak concentration of levofloxacin in lung tissue after an oral dose exceeding 500 mg is approximately 11.3 µg/mL, achieved within 4–6 hours after administration. Concentrations in lung tissue exceed those in plasma.

Distribution in blister fluid. The peak concentration of levofloxacin in blister fluid after single and twice-daily oral doses of 500 mg is 4.0 and 6.7 µg/mL, respectively.

Distribution in cerebrospinal fluid. Levofloxacin poorly penetrates into cerebrospinal fluid.

Distribution in prostate tissue. After oral administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue are 8.7 µg/mL, 8.2 µg/mL, and 2 µg/mL at 2 hours, 6 hours, and 24 hours, respectively; the mean prostate/plasma concentration ratio is 1.84.

Urine concentration. Mean concentrations of levofloxacin in urine over 8–12 hours after single oral doses of 150 mg, 300 mg, or 500 mg are 44 µg/mL, 91 µg/mL, and 200 µg/mL, respectively.

Metabolism. Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the total drug excreted in urine.

Elimination. After oral administration, levofloxacin is eliminated from plasma very slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose is excreted unchanged). There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration.

Levofloxacin exhibits linear pharmacokinetics in the dose range of 50 to 600 mg.

Clinical characteristics.

Indications.

Floxium® is indicated for the treatment in adults of infections caused by microorganisms sensitive to levofloxacin:

• acute bacterial sinusitis;
• exacerbation of chronic obstructive pulmonary disease, including bronchitis;
• community-acquired pneumonia;
• uncomplicated cystitis;
• complicated skin and soft tissue infections.

For the treatment of the above-mentioned infections, the drug should be used only when other antibacterial agents, typically prescribed for initial treatment of these infections, cannot be used;

• complicated urinary tract infections (including acute pyelonephritis);
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment.

Floxium® in this pharmaceutical form (tablets) may be used to complete the course of therapy in patients who have shown improvement during initial treatment with Floxium® infusion solution.

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to levofloxacin, to other fluoroquinolones, or to any component of the drug.

Epilepsy.

Tendon damage associated with prior use of fluoroquinolones.

Pediatric age.

Pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

Iron salts, zinc salts, antacids containing magnesium and aluminum, didanosine.

Absorption of levofloxacin is significantly reduced when administered concomitantly with iron salts and antacids containing magnesium or aluminum, or with didanosine (only formulations containing buffering agents of aluminum or magnesium). Concurrent administration of fluoroquinolones with multivitamins containing zinc leads to reduced oral absorption.

Tablets should be taken at least 2 hours after administration of products containing divalent or trivalent cations, such as iron salts or antacids containing magnesium or aluminum. Calcium carbonate had minimal effect on the absorption of orally administered levofloxacin.

Sucralfate

The bioavailability of levofloxacin is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to administer sucralfate 2 hours after taking Floxium® tablets.

Theophylline, fenbufen, or similar non-steroidal anti-inflammatory drugs (NSAIDs)

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant use of quinolones and theophylline, NSAIDs, or other agents that lower the seizure threshold.

Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen than when levofloxacin was administered alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.

Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% with probenecid. This is explained by the fact that both drugs can block tubular secretion of levofloxacin. However, in studies, statistically significant kinetic differences did not have clinical significance.

Levofloxacin should be prescribed with caution when used concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other drugs

It is known that no clinically significant effect on the pharmacokinetics of levofloxacin occurs when levofloxacin is used concomitantly with calcium carbonate, digoxin, glyburide, or ranitidine.

Effect of levofloxacin on other medicinal products

Cyclosporine

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased international normalized ratio (INR) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concurrently.

Medicinal products that prolong the QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics); see section "Special precautions".

Other significant information

No effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.

Food intake

No clinically significant interaction with food has been observed. Therefore, Floxium® tablets may be taken independently of food intake.

Special precautions for use.

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to agents containing quinolones or fluoroquinolones. Treatment of such patients should only be initiated if no alternative treatment options are available and after careful benefit/risk assessment.

Long-term, disabling and potentially irreversible serious adverse reactions

Very rarely, patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, have experienced long-term (lasting several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems (particularly musculoskeletal, nervous, psychiatric and sensory organs). If signs or symptoms of any serious adverse reaction occur, the medicinal product should be discontinued immediately and medical advice sought.

Aortic aneurysm and dissection, and valvular regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and cases of regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions"). Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions, such as:

• risk factors for both aortic aneurysm/dissection and valvular regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis;
• risk factors for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;
• risk factors for valvular regurgitation/insufficiency: infective endocarditis.

The risk of aortic aneurysm, dissection and rupture may be increased in patients concurrently receiving systemic corticosteroids.

Patients should seek immediate medical attention at an emergency department if they experience sudden abdominal, chest or back pain. Patients should be advised to seek immediate medical help if they develop acute shortness of breath, new onset of palpitations, or develop abdominal or lower limb edema.

Methicillin-resistant S. aureus (MRSA)

There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant S. aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin.

Levofloxacin may be used for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis if these infections have been appropriately diagnosed.

Resistance to fluoroquinolones in E. coli (the most common cause of urinary tract infections) varies across different countries. Local prevalence of fluoroquinolone resistance in E. coli should be taken into account when prescribing fluoroquinolones.

For pulmonary anthrax, use of the drug is based on in vitro susceptibility data for Bacillus anthracis, animal experimental data, and limited human experience. Physicians should consider national and/or international consensus guidelines on the treatment of anthrax.

Tendinitis and tendon rupture

Tendinitis, which may lead to tendon rupture including Achilles tendon, may rarely occur during quinolone therapy. Tendonitis and tendon ruptures, sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones. Cases of tendinitis and tendon ruptures have been reported even several months after discontinuation of treatment in patients who received daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with transplanted organs, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

If signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment with the drug should be discontinued and alternative therapy considered. The affected limb should be appropriately managed (e.g., immobilization of the tendon) (see section "Contraindications" and "Adverse reactions"). Corticosteroids should not be used if signs of tendinopathy occur.

Myoclonus

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately at the first sign of myoclonus, and appropriate treatment initiated.

Blood disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia or agranulocytosis, may develop during treatment with levofloxacin (see section "Adverse reactions"). If any of these disorders are suspected, blood counts should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent and/or hemorrhagic, during or after treatment (up to several weeks after completion of therapy) may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, the drug should be discontinued immediately and supportive therapy initiated as soon as possible, and specific therapy (e.g., oral vancomycin) if necessary.

Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Levofloxacin is contraindicated in patients with a history of epilepsy. As with other quinolones, Floxium® should be used with extreme caution in patients predisposed to seizures, such as patients with central nervous system disorders, those receiving concomitant therapy with phenylbutazone and similar NSAIDs, or drugs that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin treatment should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions when treated with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in such patients and possible development of hemolysis should be monitored.

Patients with renal impairment

Since levofloxacin is primarily eliminated via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency); see section "Dosage and administration".

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose (see section "Adverse reactions"). In such cases, patients should discontinue treatment immediately and seek medical advice.

Severe skin reactions

Severe skin reactions have been reported with levofloxacin use, including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be fatal. Before initiating treatment, patients should be informed about signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, levofloxacin treatment should be discontinued immediately and alternative therapy considered. Patients who have experienced such reactions as SJS, TEN or DRESS during levofloxacin use should never be re-exposed to levofloxacin.

Alterations in blood glucose levels

Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in patients with diabetes mellitus receiving concomitant oral hypoglycemic agents (including glyburide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be monitored in patients with diabetes mellitus.

Prevention of photosensitization

Cases of photosensitization have been reported with levofloxacin use. To avoid this, patients should avoid exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during levofloxacin treatment and for 48 hours after discontinuation of the drug.

Patients receiving vitamin K antagonists

Due to possible increases in coagulation test parameters (prothrombin time/INR) and/or bleeding in patients taking levofloxacin in combination with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored when these drugs are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin.

In very rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken.

Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation

Floxium® should be used with caution in patients with known risk factors for QT interval prolongation, such as:

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval; therefore, caution is required when using levofloxacin in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration", "Elderly patients", "Overdose", "Adverse reactions").

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy, leading to paresthesia, hypoesthesia, dysesthesia or weakness, has been reported in patients receiving fluoroquinolones, including levofloxacin. If a patient experiences such neuropathic symptoms as pain, burning, tingling, numbness or weakness, levofloxacin should be discontinued and medical advice sought to prevent irreversible damage.

Hepatobiliary disorders

Cases of necrotizing hepatitis up to life-threatening liver failure have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and seek medical advice if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatal cases and the need for respiratory support, have been reported post-marketing in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disorders

There have been reports (22 cases worldwide) of retinal detachment associated with the use of fluoroquinolone antibiotics.

If visual disturbances or other ocular effects occur, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction rate when driving or operating machinery", "Adverse reactions").

Superinfection

With levofloxacin use, particularly prolonged use, overgrowth of resistant microorganisms may occur. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory tests

In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Positive opiate test results may require confirmation by more specific methods.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may result in false-negative bacteriological test results in patients with tuberculosis.

Excipients (lactose)

The drug contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of levofloxacin in pregnant women are limited.

Due to the lack of human studies and the potential for quinolone-induced damage to cartilage in the growing organism, Floxium® is contraindicated in pregnant women and in women who are breastfeeding.

If pregnancy is established during treatment with Floxium®, this should be reported to the physician.

Breastfeeding. Floxium® is contraindicated during breastfeeding.

Information on the excretion of levofloxacin in breast milk is insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolone-induced damage to cartilage in the growing organism, Floxium® should not be administered to women who are breastfeeding.

Fertility.

Levofloxacin did not cause disorders of fertility or reproductive function in rats.

Ability to affect reaction rate when driving or operating machinery.

Patients who drive vehicles or operate machines and equipment should be aware of possible adverse nervous system reactions (dizziness/vertigo, numbness, somnolence, confusion, visual and hearing disturbances, motor disturbances).

Dosage and Administration

Floxium® tablets are taken once or twice daily. The dosage depends on the type and severity of infection and the susceptibility of the probable causative agent.

Floxium® in this pharmaceutical form (tablets) may be used to complete the course of therapy in patients who have shown improvement during initial treatment with Floxium® infusion solution, using the same dosage.

The duration of treatment depends on the course of the disease and should not exceed 14 days. It is recommended to continue administration of the drug for at least 48–72 hours after normalization of body temperature or after microbiological testing has confirmed eradication of the causative pathogen.

Floxium® tablets should be swallowed whole without chewing, with an adequate amount of liquid. For convenient dosing, the tablet may be divided along the score line. The tablets may be taken regardless of food intake.

The drug should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for formulations containing aluminum or magnesium in buffering agents), and sucralfate (see section "Interaction with other medicinal products and other types of interactions").

Table 2

Recommended dosage for adult patients with normal renal function and creatinine clearance above 50 mL/min

Special populations

Table 3

Dosing for patients with impaired renal function with creatinine clearance less than 50 ml/min

1 Additional doses are not required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily eliminated by the kidneys.

Dosing in elderly patients. If renal function is normal, dose adjustment is not required (see section "Special precautions").

Children. FloxiumÒ is contraindicated in children and adolescents due to the risk of joint cartilage damage.

Overdose.

Symptoms of levofloxacin overdose include disturbances of the central nervous system (confusion, dizziness, altered consciousness, seizures, myoclonus); gastrointestinal reactions such as nausea and mucosal erosion; possible QT interval prolongation. Hallucinations and tremor may also occur.

Treatment: symptomatic. ECG monitoring should be considered due to the potential for QT interval prolongation. Antacids should be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis or continuous ambulatory peritoneal dialysis (CAPD), is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse Reactions

The frequency of adverse effects was determined according to the following criteria: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1,000 to <1/100), rare (from ≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations:

Uncommon: fungal infections, including Candida species; overgrowth of resistant microorganisms.

Blood and lymphatic system disorders:

Uncommon: leucopenia, eosinophilia;
Rare: thrombocytopenia, neutropenia;
Frequency not known: bone marrow depression, including aplastic anemia, agranulocytosis, pancytopenia, hemolytic anemia.

Immune system disorders:

Rare: angioedema, hypersensitivity;
Frequency not known: anaphylactic shock, anaphylactoid shock.

Anaphylactic and anaphylactoid reactions may occasionally occur even after the first dose.

Metabolism and nutrition disorders:

Uncommon: anorexia;
Rare: hypoglycemia, particularly in patients with diabetes;
Frequency not known: hyperglycemia, hypoglycemic coma.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH, rarely observed).

Mental disorders:

Common: insomnia;
Uncommon: nervousness, confusion, anxiety;
Rare: psychotic disorders (including hallucinations, paranoia), depression, agitation, unusual dreams, night terrors;
Frequency not known: mania, psychotic reactions with self-destructive behavior, including suicidal ideation or actions.

Nervous system disorders*:

Common: headache, dizziness;
Frequency not known: somnolence, tremor, dysgeusia (subjective taste disturbance);
Rare: convulsions, paraesthesia;
Frequency not known: myoclonus, sensory or sensorimotor peripheral neuropathy, parosmia (disturbance of smell), including anosmia (loss of smell), dyskinesia, extrapyramidal disorders, ageusia (loss of taste), syncope, benign intracranial hypertension.

Eye disorders*:

Rare: visual disturbances such as blurred vision, visual blurring;
Frequency not known: transient loss of vision.

Cases of retinal detachment have been reported (see section "Special Warnings and Precautions for Use").

Ear and labyrinth disorders*:

Uncommon: vertigo;
Rare: hearing disturbances;
Frequency not known: tinnitus, hearing loss.

Cardiac disorders**:

Rare: tachycardia, palpitations;
Frequency not known: ventricular tachycardia, which may lead to cardiac arrest, torsade de pointes ventricular tachycardia (mainly observed in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG (see sections "Special Warnings and Precautions for Use. QT interval prolongation" and "Overdose").

Vascular disorders**:

Rare: arterial hypotension.

Respiratory system disorders:

Uncommon: bronchospasm;
Frequency not known: dyspnea, allergic pneumonitis.

Gastrointestinal disorders:

Common: diarrhea, nausea, vomiting;
Uncommon: abdominal pain, dyspepsia, bloating, constipation;
Frequency not known: hemorrhagic diarrhea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis, pancreatitis.

Hepatobiliary disorders:

Common: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT);
Uncommon: increased blood bilirubin;
Frequency not known: jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), predominantly in patients with severe underlying diseases, hepatitis.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus, urticaria, hyperhidrosis;
Frequency not known: skin hyperpigmentation, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS, rarely observed), localized skin rash induced by drugs (see section "Special Warnings and Precautions for Use"), exudative polymorphic erythema, photosensitivity reactions, leukocytoclastic vasculitis, stomatitis.

Skin and mucosal reactions may occasionally occur even after administration of the first dose.

Musculoskeletal and connective tissue disorders*:

Uncommon: arthralgia, myalgia;
Rare: tendon disorders, including inflammation (tendinitis, e.g., Achilles tendon), muscle weakness, which may be particularly significant in patients with severe myasthenia gravis;
Frequency not known: rhabdomyolysis, tendon rupture (e.g., Achilles tendon), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders:

Uncommon: increased serum creatinine levels;
Rare: acute renal failure (e.g., due to interstitial nephritis).

General disorders*:

Uncommon: asthenia;
Rare: increased body temperature (pyrexia);
Frequency not known: pain (including back, chest, and limb pain).

Other adverse effects associated with fluoroquinolone use include porphyria attacks in patients with pre-existing porphyria.

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, have experienced long-lasting (for several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (including tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, and disturbances of hearing, vision, taste, and smell).

** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Special Warnings and Precautions for Use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

5 or 10 tablets per blister, 1 blister per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of its business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.